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The prospect of effective immunotherapies for the treatment of patients with cancer is now becoming a clinical reality. Different major phenotypes of tumor microenvironment are emerging and could require distinct immunotherapeutic interventions for maximal therapeutic effect. In the T-cell infiltrated tumors context, monoclonal antibody blocking the PD-1/PD-L1 pathway, like nivolumab or lambrolizumab, have shown very promising clinical efficacy for patients with metastatic melanoma (MM), Non Small Cell Lung cancer and renal cell carcinoma (1, 2). Recently, the combination of nivolumab and ipilimumab (anti CTLA-4) has demonstrated a strong synergy in MM patients (3). Thus, blocking peripheral tolerance mechanisms such as CTLA-4 and PD1 molecules seems to be a very promising strategy to cure such cancers. Many combinations with other immunotherapeutic interventions seem encouraging to be evaluated in early clinical trials. Leveraging or consolidating the driving forces between the efficacy of such checkpoint inhibitors with novel activating or inhibiting immunomodulatory agents is crucial and has to be based on relevant pharmacological and preclinical models. RLI is a sushi-IL-15Rα/IL-15 fusion protein that mimics the IL-15 transpresentation (4). In this study, the immunomodulatory activities induced by RLI were evaluated in vivo in mice and ex-vivo on human samples. We showed that RLI induced a strong expansion and increased effector functions and differentiation of NK and CD8+ T cells without any induction/activation of regulatory CD4+ T cells (Treg). Comparison of equimolar doses of RLI, IL-15 and IL-2, led to the conclusion that RLI is much more effective than IL-15 for the induction of NK and CD8+ T cells and increased the ratio of NK to Treg cells. Beside, RLI appeared as a safe, specific and potent IL-15Rβ/γ receptor agonist. We then investigated potential synergy with anti-PD1 treatment in the CT26 preclinical mouse tumor model. Anti-PD1 and RLI concomitant treatment induced 31% of complete tumor regressions (CR) in the tumor model, while anti-PD1 as standalone treatment induced 6% of CR. The underlying mechanisms of this synergy will be presented during the AACR meeting. Altogether, this work provides evidence that RLI can enhance anti-tumor activity of anti-PD1 treatment. As RLI was shown to present a favorable safety profile in different animal species, these results are very encouraging and warrant its investigation in early clinical trials in the coming years. (1) Topalian SL et al. N Engl J Med. 2012 (2) Hamid O et al. N Engl J Med. 2013 (3) Wolchok JD et al. N Engl J Med. 2013 (4) Mortier E, et al. J Biol Chem. 2006 Citation Format: Mélanie Desbois, Coralie Beal, Clelia Coutzac, Magali Terme, Geraldine Teppaz, Sebastien Morisseau, David Bechard, Erwan Mortier, Nathalie Chaput. RLI, a sushi-IL-15Rα/IL-15 fusion protein, is a potent immunomodulatory agent on NK and CD8+ T cells and synergizes with anti-PD1 treatment in preclinical mouse tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2577. doi:10.1158/1538-7445.AM2014-2577